Veno-occlusive Research Articles

A phase I trial of dose-adjusted EPOCH plus inotuzumab ozogamicin (InO) in adults with relapsed/refractory (R/R) B lymphoblastic leukemia/lymphoma (B-ALL).

7007 Background: Outcomes for adults with R/R B-ALL remain poor, with existing options limited by efficacy and safety. InO has been combined with low-intensity chemotherapy, the benefit of which is unclear. DA-EPOCH is safe and active as frontline therapy in adults with ALL, so we combined this with InO in adults with R/R B-ALL (NCT03991884). Aims: The primary objective was to estimate the maximum tolerated dose (MTD) of InO when added to DA-EPOCH. Methods: Eligible patients (pts) were adults with R/R CD22+ B-ALL with ≥5% blood or marrow (BM) blasts or ≥1 site of measurable extramedullary disease (EMD); other eligibility criteria included ECOG ≤2 and no history of sinusoidal obstructive syndrome (SOS) or chronic liver disease. DA-EPOCH was given on days (d) 1-5 with GCSF. After cycle 1, dose adjustments to EPOCH were made based on hematologic nadirs from the prior cycle. Three dose levels (DL) of InO were studied, with InO given on d 8 + 15 as follows (respectively): 0.3 + 0.3 mg/m2 (DL1); 0.6 + 0.3 mg/m2 (DL2); and 0.6 + 0.6 mg/m2 (DL3). Up to 4 28-d cycles were given. The MTD was the highest DL of InO that yielded ≤33% rate of dose limiting toxicity (DLT), defined as grade 4+ non-heme treatment-related adverse events (TRAEs), any SOS regardless of timing, unable to complete 1 cycle due to TRAE, and treatment delays > 3 weeks. After the first 5 pts received DL1, a Bayesian Optimal Interval Design was used. Target accrual was 24 pts. BM and EMD response was assessed by NCCN criteria, with measurable residual disease (MRD) evaluated by multiparameter flow cytometry (MFC) and clonoSEQ. Results: 24 pts were screened: all were enrolled and evaluable for DLT and response. Median age was 46 (range: 28-76) years; median prior lines of therapy was 3 (range: 1-16); 13 pts (54%) had previously received allograft (HCT). 5 pts were enrolled at DL1, 8 pts at DL2, and 11 pts at DL3. There were 4 total DLTs: 1 at DL1 (grade 4 sepsis) and 3 at DL3 (grade 4 hyponatremia; delay for pancytopenia; grade 5 SOS after post-study HCT). DL3 was thus determined to be the MTD. No deaths occurred on study. Three pts (12%) had Grade 3 AST/ALT elevation; the SOS rate was 4%. Other grade 3+ non-heme TRAEs seen in >1 pt included infections (6 pts; 9 events), neutropenic fever (7; 8), and oral mucositis (3; 4). In the pts with ≥5% blood/BM blasts (n=20), the CR/CRi rate was 85%. By MFC, 70% achieved MRD- (45% after 1 cycle); using clonoSEQ, 33% were MRD-. Of the 6 pts with EMD, 83% responded (4 CR; 1 PR). The per-protocol and intent-to-treat (ITT) overall response rate was 83%. With median follow-up of 12 months (m), the median overall and relapse-free survival were 19 m and 12 m. Nine (38%) pts received post-study HCT. Conclusions: The addition of InO to DA-EPOCH in adults with heavily-pretreated R/R B-ALL is safe, with ITT response rates among the highest reported to date. Many pts proceeded to HCT. Further investigation of this combination is warranted. Clinical trial information: NCT03991884 .

A phase 3 trial of inotuzumab ozogamicin for high-risk B-ALL: Second safety phase results from Children’s Oncology Group AALL1732.

10016 Background: Inotuzumab ozogamicin (InO) is effective in adults and children with relapsed/refractory (R/R) CD22+ B-acute lymphoblastic leukemia (B-ALL). Children’s Oncology Group AALL1732 is a phase 3 randomized trial evaluating InO for newly diagnosed patients (pts) with high-risk B-ALL. Given known hepatic, hematologic, and infectious toxicities, two safety phases were completed. Methods: Pts with residual marrow disease < 0.01% by end consolidation are randomized to chemotherapy (Arm A) or chemotherapy plus 2 cycles of InO (Arm B) after consolidation and interim maintenance 1 (IM1). Modifications after safety phase 1 [SP1; McNeer et al. Blood (2021) 138 (Suppl 1):3398] included reducing InO to 1.2mg/m2/cycle, increasing hydration during IM1 on Arm B, and enhancing supportive care in delayed intensification (DI) with antimicrobials. Safety phase 2 (SP2) assessed methotrexate (MTX) clearance, treatment delays and infectious/hepatic toxicity. Planned interim analysis is reported. Results: Fifty pts were randomized and evaluable (25 Arm A, 25 Arm B). There was no difference in gr ≥3 ALT or bilirubin elevations. Sinusoidal obstruction syndrome (SOS) occurred in 4 Arm B pts during DI including 3 (1 gr 3, 2 gr 4) in DI part 2 (DI2). IM1 day 1 MTX clearance was similar 65.4 (range 52.6-154) vs 70.2 hrs (range 56.5-267) on Arm A vs B, p = 0.27. Mean duration of IM1 was 74.8 (sd 11.8) vs 84 days (sd 13.3) on Arm A vs B, p = 0.013. Arm B IM1 duration in SP2 was shorter than SP1 [90 days (sd 15.3)]. DI part 1 (DI1) duration was similar between Arms. Arm B DI2 was longer than Arm A [53.8 (sd 20.2) vs 42.6 days (sd 9.5), p = 0.025]. Sepsis occurred in DI1 in 0 Arm A and 5 Arm B pts and in DI2 in 1 Arm A and 5 Arm B pts (Table). In DI2 1 pt on each Arm had gr 5 multiorgan failure (MOF) with sepsis. In DI1 50% of Arm A and 87.5% of Arm B pts had absolute neutrophil count (ANC) < 500 (p = 0.011). In DI2 all Arm A and 92.5% of Arm B pts had ANC < 500 with longer duration on Arm B [19.3 (sd 8.1) vs 7.8 days (sd 12.4), p = 0.015]. Compliance with prophylactic antibiotics was higher on Arm B (DI1 Arm A 41.7% vs Arm B 80.9%; DI2 Arm A 52.2% vs Arm B 85%). Conclusions: While SP2 modifications improved MTX clearance and duration of IM1, SOS and infections remain concerning on Arm B, particularly during DI. Most SOS events occurred proximal to thioguanine in DI2. Neutropenia was more pronounced in DI on Arm B but compliance with antimicrobials was high. Higher sepsis rates, primarily gr 3, were observed on Arm B with no increase in gr 5 infections. Additional modifications are planned for Arm B to further mitigate toxicity during post InO chemotherapy blocks. Clinical trial information: NCT03959085 . [Table: see text]

RWD170 Understanding Burden of Veno-Occlusive Disease (VOD): Comparison of Hospital Stays with Vod Principal Versus Secondary Diagnosis

To compare hospitalizations with principal and secondary diagnosis of Veno-Occlusive Disease (VOD).

Inotuzumab ozogamicin (INO) for the treatment of measurable residual disease (MRD) in patients with B-cell acute lymphoblastic leukemia (B-ALL): Results from a phase II study.

e19008 Background: INO is effective in relapsed/refractory B-ALL and may have utility in eradicating MRD in patients (pts) in MRD-positive (MRD+ve) remission. Methods: This is a phase II trial of pts with B-ALL in complete remission (CR) with persistent MRD+ve or with MRD+ve relapse. Eligible pts were required to be MRD+ve at ≥0.01%. MRD negativity (MRD-ve) was defined as undetectable MRD by flow cytometry (sensitivity 10-4) for Philadelphia (Ph)-negative (Ph-) B-ALL and undetectable MRD by both flow and PCR for BCR:ABL1 for Ph-positive (Ph+) B-ALL. INO was given at a dose of 0.6 mg/m2 on D1 and 0.3 mg/m2 on D8 of cycle 1 and 0.3 mg/m2 on D1 and 8 of subsequent cycles (up to 6 total cycles, given every 21-28 days) along with ursodiol prophylaxis. Pts with Ph+ ALL received concomitant TKI. Results: 27 pts with MRD+ve B-ALL were treated between 11/2018 and 6/2022 (Table). 17 pts (63%) had Ph+ B-ALL (15 received ponatinib and 2 dasatinib), and 10 pts had Ph- B-ALL. 20 pts (74%) were in CR1, and 7 pts (26%) were in CR2 or beyond. 14 pts (52%) had received prior blinatumomab and 5 pts (18%) had prior stem cell transplantation (SCT). 18 pts (67%) became MRD-ve (responders), 16 after the 1st cycle and 2 after the 2nd cycle of INO. In the Ph+ group, 10/17 pts (59%) responded; another 3 pts achieved major molecular response. 8/10 (80%) pts with Ph- B-ALL responded. The median number of cycles of INO were 3 (range, 1-6). Rates of MRD response were higher in pts without prior blinatumomab (11/13 pts [80%]), compared with those with prior blinatumomab exposure (7/14 [50%]) ( P=0.06). After a median follow-up of 21 months, 13/18 responding pts (72%) are in ongoing MRD-ve CR. Among the 18 responders, 6 pts underwent allogeneic stem cell transplant (ASCT) after a median of 3 cycles of INO (range, 1-4); all were in MRD-ve CR at the time of ASCT. 4/18 responders (22%) relapsed, 1 of whom relapsed after ASCT. Median RFS and OS for the whole group were not reached; estimated 2-year RFS and OS were 61% and 62%, respectively. 2-year OS for responders and non-responders were 76% and 50% (P=0.34), respectively. 2-year RFS for pts with or without prior blinatumomab was 23% and 91%, respectively; P=0.04. No grade 4 non-hematological toxicities were observed. 1 pt (who had a history of prior ASCT) had grade 3 sinusoidal obstruction syndrome. Conclusions: Low-dose, fractionated INO is effective at eradicating MRD in pts with B-ALL and can result in durable MRD-ve remissions. Clinical trial information: NCT03441061 . [Table: see text]

Phase II trial of mini-hyper-CVD-inotuzumab (InO) followed by blinatumomab (blina) consolidation in patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL).

e19037 Background: Promising results were seen with low intensity chemotherapy mini-Hyper-CVD (mini-HCVD) in combination with InO in R/R ALL. Adding blina may further improve outcomes. Methods: Pts with R/R Philadelphia-negative B-ALL were treated with mini-HCVD (Cycles 1, 3, 5, 7) and methotrexate/cytarabine (Cycles 2, 4, 6, 8) for 8 cycles. Initially, InO was given on Day (D) 3 of the first 4 cycles at the dose of 1.8-1.3 mg/m2 in Cycle (C) 1, followed by 1.3-1.0 mg/m2 in subsequent cycles. POMP maintenance was for a total of 3 yrs. Protocol was amended after pt #67 to add 4 cycles of blina after 4 cycles of mini-HCVD+InO. InO was given on D2 and 8 at the dose of 0.6 and 0.3 mg/m2 in C1, and then on D2 and 8 at the dose of 0.3 mg/m2 in subsequent cycles; blina was given at standard dose in C5-8. Maintenance was reduced to 12 cycles of POMP with 1 cycle of blina after each 3 cycles of POMP for a total of 4 cycles. Rituximab was given for CD20+ disease. All pts received 8 doses of intrathecal chemotherapy. Results: Between 2/2013 and 7/2021, 110 pts were treated. Patient characteristics are shown in the table. 79 (72%) pts were treated in Salvage (S) 1, and 31 (28%) in S2+. 21 (19%) pts had received prior ASCT. 91 (83%) pts responded (complete remission, 63%). The overall response rate was 93% in S1, 59% in S2, and 57% in S3+. The rates of MRD negativity by flow were higher in S1 vs S2+ (89% vs 67%; P=0.047). 53 (48%) pts underwent ASCT. After a median follow-up of 48 months (mo) (range, 9-115), the median OS and RFS were 17 mo (4-yr, 36%) and 13 mo (4-yr, 37%), respectively. Pts in S1 had better OS compared with S2+ (4-yr OS, 43% vs 18%; P<0.001). The 4-yr RFS was 38% in S1 and 27% in S2+ ( P=0.14). In S1, 41 pts were treated before the amendment and 38 after the amendment; their 4-yr OS was 41% and 48% ( P=0.99), and their 4-yr RFS was 39% and 36%, respectively ( P=0.95). A landmark analysis of pts who achieved remission showed no survival difference between pts who did or did not undergo ASCT, with 4-yr OS of 49% and 48% ( P=0.98), and 4-yr RFS of 46% and 37% ( P=0.68), respectively. Sinusoidal obstruction syndrome (SOS) was noted in 10 (9%) pts, and its incidence decreased from 13% with single dose of InO to 2% with lower and fractionated doses of InO ( P=0.056). Conclusions: The combination of mini-HCVD and reduced-dose InO with sequential blina improved the outcomes of pts with R/R ALL. The new treatment schedule resulted in a lower rate of SOS compared to the original schedule. Clinical trial information: NCT01371630 . [Table: see text]

UCHMC 1812: A phase 1b trial of CPX-351 plus gemtuzumab ozogamicin for relapsed/refractory acute myeloid leukemia.

7024 Background: Gemtuzumab ozogamicin (GO) is effective in favorable-risk acute myelogenous leukemia (AML), while its activity is limited in higher-risk AML in part due to multi-drug resistance (MDR) mechanisms, particularly P-glycoprotein efflux pumps. CPX-351 provides a survival benefit in secondary AML, a disease characterized by high MDR activity. The objective of this trial is to utilize CPX-351 as a bulk cytoreduction agent, to first reduce the high MDR leukemia clones, followed by sequential treatment with GO in a more favorable leukemia environment. Methods: This was a multicenter phase Ib trial of CPX-351 plus GO in relapsed/refractory (R/R) AML patients with standard 3+3 dose escalation design (NCT03904251). Cohort A was treated with CPX-351 100 u/m2 on days 1, 3, and 5 plus GO 3 mg/m2 (max 4.5 mg) on day 7. Cohort B was treated with the same regimen plus an additional dose of GO 3 mg/m2 on day 4. The primary endpoint was the maximum tolerated dose (MTD), defined as < 2 dose limiting toxicities (DLTs) in the highest dose cohort. Secondary endpoints were IWG complete remission (CR) rate at day 28-42, liver veno-occlusive disease (VOD) rate diagnosed by the Baltimore criteria, and time of hematologic recovery (defined as ANC > 1000/uL and platelet count > 100,000/uL). Patients were enrolled at 4 University of California Hematologic Malignancies Consortium (UCHMC) centers: UC Los Angeles, UC San Francisco, UC Davis, and UC Irvine. Results: Thirteen participants were enrolled. The median age was 63 years (range 29-75). Eleven had relapsed disease, and two had refractory disease. Most received one prior line of therapy (n = 9). Seven had ELN 2022 adverse-risk disease at initial diagnosis, and two had intermediate-risk disease. The MTD was not reached. DLTs were observed in 1/6 participants in cohort A (grade 3 rash), and 1/6 participants in cohort B (grade 5 intracranial hemorrhage in the setting of severe thrombocytopenia). There were no cases of liver VOD. Of 12 evaluable participants, 4 achieved CR (33%), of whom 3 were negative for measurable residual disease by multiparametric flow cytometry, and 1 one achieved partial remission. The median age of responders was 30 years (range 28-65). The median time to return of normal hematopoiesis in those who achieved remission was 37 days (range 36-43). Three participants received allogeneic hematopoietic cell transplant (alloHCT) following investigational therapy: one remains in remission 34 months post-transplant, one died of infectious complications shortly after alloHCT, and one relapsed at day +60. Conclusions: CPX-351 plus two doses of GO 3 mg/m2 is a feasible treatment with acceptable toxicity and reasonable marrow recovery kinetics. However, only three participants went on to curative alloHCT. Further evaluation for efficacy in a larger patient population is needed to determine the utility of this regimen in R/R AML. Clinical trial information: NCT03904251 .

RWD24 Veno-Occlusive Disease (VOD) Incidence and Treatment Trends Insights from Latest Systematic Review of Case Reports (2018-2023)

For ultra rare diseases independent case reports provide useful real-world evidence on disease burden and treatment trends. The objective of this review was to understand incidence and treatment trends for Veno-Occlusive Disease (VOD) using latest published case reports.

First-in-human study of ABBV-011, a seizure-related homolog protein 6 (SEZ6)–targeting antibody-drug conjugate, in patients with small cell lung cancer.

3002 Background: Small cell lung cancer (SCLC) has a dismal prognosis and new therapies are urgently needed. SEZ6 is a transmembrane protein expressed in SCLC tumors that may be used as a therapeutic target. ABBV-011 is an antibody-drug conjugate (ADC) targeting SEZ6 with a calicheamicin payload, which has shown antitumor activity in preclinical models of SCLC. Preliminary results from the monotherapy dose-escalation and -expansion cohorts of the first-in-human ABBV-011 study are presented. Methods: Phase 1, open-label, multicenter study (NCT03639194) of ABBV-011 alone or in combination with budigalimab, a programmed cell death 1 inhibitor. Primary objectives were to assess the safety and tolerability and to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose of ABBV-011. Adults (≥18 years) with relapsed/refractory SCLC (1–3 lines of prior therapy) were enrolled. Dose escalation was guided by Bayesian continual reassessment method. ABBV-011 was administered intravenously at doses from 0.3 to 2.0 mg/kg once every 3 weeks. Dose expansion was conducted in SEZ6-selected patients. Results: At data cutoff on August 22, 2022, 99 patients were treated with ABBV-011 monotherapy. Median age was 63 years (range, 41–79), 50% of patients were male, and 68% had received ≥2 prior therapies. ABBV-011 ADC pharmacokinetics were approximately dose-proportional with an elimination half-life of 4.6 days across the dose range of 0.3–2.0 mg/kg. In dose escalation (n=26), 1 patient had a dose-limiting toxicity of grade (G) 3 fatigue at 2.0 mg/kg. We report safety and efficacy results for 40 patients in the dose-expansion 1.0-mg/kg ABBV-011 cohort. Median duration of treatment was 12 weeks (range, 1.9–63.3). Treatment-emergent adverse events (TEAEs) occurred in 39 (98%) patients, the most frequent being fatigue (48%), nausea (45%), anorexia (38%), thrombocytopenia (38%), and vomiting (35%). G3 TEAEs occurred in 18 (45%) patients, the most frequent being fatigue, thrombocytopenia, and neutropenia (10% each); 1 G4 TEAE of dyspnea was reported. Seven patients died due to malignant neoplasm/disease progression (n=6) or respiratory distress (n=1); none were related to ABBV-011. Hepatotoxicity was observed, including G≥2 TEAEs of hyperbilirubinemia (18%), increased gamma-glutamyltransferase (8%), ascites (5%), veno-occlusive liver disease (3%), and portal hypertension (3%). Confirmed objective response rate was 25% (10 partial responses [PR]), with median duration of response of 4.2 months (95% CI: 2.6, 6.7). Clinical benefit rate (CBR) was 65% (10 PR and 16 stable disease) and CBR lasting >12 weeks was 43%. The median progression-free survival was 3.5 months. Conclusions: The MTD was not reached and ABBV-011 was well tolerated at 1.0 mg/kg with promising antitumor activity observed. Further evaluation of ABBV-011 is ongoing. Clinical trial information: NCT03639194 .

Beyond Busulfan: Building a Better Conditioner for Bone Marrow Transplantation

Beyond Busulfan: Building a Better Conditioner for Bone Marrow Transplantation

Mini-hyper-CVD plus inotuzumab ozogamicin (InO), with or without blinatumomab (Blina), in older patients with newly diagnosed Philadelphia chromosome (Ph)-negative B-cell acute lymphoblastic leukemia (ALL): Updates from a phase II trial.

e19025 Background: The overall survival (OS) of patients (pts) with relapsed/refractory B-ALL has improved with the introduction of InO and Blina. Compared to conventional chemotherapy, the incorporation of these agents into the frontline setting of older pts with ALL may allow the use of less chemotherapy and potentially improve outcomes. Methods: Adults ≥60 yrs with newly diagnosed Ph-negative B-ALL received mini-Hyper-CVD (mini-HCVD) for up to 8 cycles. Initially, InO was given at 1.3-1.8mg/m2 on Day (D) 3 of Cycle (C) 1 and 0.8-1.3mg/m2 on D3 of C2-4. Rituximab (if CD20+) and prophylactic IT chemotherapy were given for the first 4 cycles. Responders received POMP maintenance for up to 3 yrs. Beginning with pt #50, InO was given in fractionated doses each cycle (0.6 mg/m2 on D2 and 0.3 mg/m2 on D8 of C1; 0.3 mg/m2 on D2 and 8 of C2-4) and 4 cycles of Blina were given following 4 cycles of mini-HCVD plus InO. Maintenance was with 12 cycles of POMP and 4 cycles of Blina (1 cycle of Blina after 3 cycles of POMP). Results: 83 pts were treated, of whom 6 were in complete remission (CR) at enrollment(Table 1). Among 77 evaluable pts, 76 (99%) responded (CR, 90%). Among responders, the rates of MRD negativity by flow cytometry were 79% and 94% after C1 and overall, respectively. No early death was observed. Among 82 pts in remission, 11 (13%) relapsed, 4 (5%) underwent ASCT, 34 (41%) remain in ongoing continuous remission, 33 (41%) died in remission, of whom 9 died after developing MDS/AML. Three pts (4%) developed veno-occlusive disease, 2 after subsequent ASCT. After a median follow-up of 65 months (range, 6-126), the 5-yr continuous remission duration and OS rates were 78% and 48%, respectively. Age ≥70 and adverse cytogenetics were associated with worse outcomes. The inferior outcome in pts ≥70 yrs was primarily attributed to higher rates of death in CR. The 5-yr OS for pts age 60-69 yrs without adverse cytogenetics (n=40), age 60-69 with adverse cytogenetics (n=15), age ≥70 without adverse cytogenetics (n=24) and age ≥70 with adverse cytogenetics (n=4) were 72%, 27%, 38% and 0%, respectively. Conclusions: Favorable outcomes were observed in older pts with newly diagnosed Ph-negative ALL treated with mini-HCVD plus InO, with or without Blina. The 5-yr OS was 48%. Clinical trial information: NCT01371630 . [Table: see text]

PEG-asparaginase treatmentregimens for acute lymphoblastic leukaemia in children: a network meta-analysis.

PEG-asparaginase treatmentregimens for acute lymphoblastic leukaemia in children: a network meta-analysis.

Transjugular Intrahepatic Portosystemic Shunt Benefits for Hepatic Sinusoidal Obstruction Syndrome Associated with Consumption of Gynura Segetum: a Propensity Score-Matched Analysis.

Pyrrolidine alkaloids-related hepatic sinusoidal obstruction syndrome (PA-HSOS) is associated with a high mortality rate without standardized therapy. The efficacy of transjugular intrahepatic portosystemic shunts (TIPS) remains controversial. The study aimed to explore the risk factors influencing the clinical response in patients with PA-HSOS related to Gynura segetum (GS) to assess the disease prognosis at an early stage and to evaluate the efficacy of TIPS in these patients. This study retrospectively enrolled patients diagnosed with PA-HSOS between January 2014 and June 2021 with a clear history of exposure to GS. Univariate and multivariate logistic regression analyses were used to evaluate the risk factors influencing the clinical response in patients with PA-HSOS. Propensity score matched (PSM) was performed to compensate for differences in baseline characteristics between patients with and without TIPS. The primary outcome was the clinical response defined as the disappearance of ascites with normal total bilirubin levels and/or a reduction of elevated transaminase levels < 50% within 2weeks. A total of 67 patients were identified in our cohort with a clinical response rate of 58.2%. Of these, thirteen patients were assigned to the TIPS group and 54 to the conservative treatment group. Logistic regression analysis revealed that TIPS treatment (P = 0.047), serum globulin levels (P = 0.043), and prothrombin time (P = 0.001) were independent factors influencing clinical response. After PSM, there was a higher long-term survival rate of patients (92.3% vs. 51.3%, P = 0.021) and a shorter hospital stay (P = 0.043), but a high trend in hospital costs (P = 0.070) in the TIPS group. The 6-month survival probability in patients undergoing TIPS therapy was more than ninefold higher than in patients without receiving that treatment [hazard ratio (95% CI) = 9.304 (4.250, 13.262), P < 0.05]. TIPS therapy may be an effective treatment option for patients with GS-related PA-HSOS.

Liver cirrhosis following oxaliplatin-based adjuvant chemotherapy for rectal cancer.

Oxaliplatin is a third-generation platinum-based antineoplastic drug that is widely used to treat patients with colorectal cancer. Reported adverse reactions include hepatic sinusoidal obstruction syndrome and liver fibrosis, but there are few reports of cirrhosis associated with chemotherapy. In addition, the pathogenesis of cirrhosis remains unclear. We report a case of suspected oxaliplatin-induced liver cirrhosis, an adverse reaction that has not been previously reported. A 50-year-old Chinese man was diagnosed with rectal cancer and underwent laparoscopic radical rectal cancer surgery. The patient had a history of schistosomiasis, but history and serology showed no evidence of chronic liver disease. However, after five oxaliplatin-based chemotherapy cycles, the patient presented dramatic changes in liver morphology and developed splenomegaly, massive ascites, and elevated CA125 levels. Four months after discontinuing oxaliplatin, the patient's ascites had decreased significantly and CA125 levels declined from 505.3 to 124.6 mU/mL. After 15 weeks of follow-up, CA125 levels decreased to the normal range, and there has been no increase in ascites in this patient. Oxaliplatin-induced cirrhosis may be a serious complication and should be discontinued based on clinical evidence.

Review of acute kidney injury and progression to chronic kidney disease in pediatric patients undergoing hematopoietic cell transplant.

While acute kidney injury (AKI) after hematopoietic cell transplant (HCT) has been well-described in pediatric patients, literature regarding the long term renal consequences of HCT-related AKI, the development of chronic kidney disease (CKD), and CKD care in pediatric patients post-HCT is limited. CKD affects almost 50% of patients after HCT with multifactorial etiology including infection, nephrotoxic medications, transplant-associated thrombotic microangiopathy, graft-versus-host disease, and sinusoidal obstruction syndrome. As renal function declines in CKD, eventually progressing to end stage kidney disease (ESKD), mortality increases and is more than 80% among patients requiring dialysis. Using society guidelines and current literature, this review summarizes definitions and etiologies of and management strategies among patients with AKI and CKD post-HCT with an emphasis on albuminuria, hypertension, nutrition, metabolic acidosis, anemia, and mineral bone disease. The goal of this review is to aid early identification and intervention in patients with renal dysfunction prior to development of ESKD, and to discuss ESKD and renal transplant in these patients post-HCT.

Prospective assessment of risk biomarkers of sinusoidal obstruction syndrome after hematopoietic cell transplantation.

Currently, no laboratory tests exist to stratify for the risk of developing sinusoidal obstruction syndrome (SOS), an early endothelial complication after hematopoietic cell transplantation (HCT). Risk biomarkers of SOS have not been verified in a prospective cohort accounting for differences between practices across institutions. Herein, we aimed to define risk groups for SOS occurrence using three proteins: L-Ficolin, Hyaluronic Acid (HA), and Stimulation-2 (ST2). Between 2017 to 2021, we prospectively accrued 80 pediatric patients across 4 US centers. Biomarkers were tested by ELISA blind to patient groupings and associated with SOS incidence at day 35 post-HCT, and overall survival (OS) at day 100 post-HCT. Cutpoints were identified using retrospective cohorts and applied to the prospective cohort. Combination of the three biomarkers measured at day 3 post-HCT in the prospective cohort provided 80% (95%CI, 55-100%) sensitivity and 73% (95%CI, 62-83%) specificity for risk of SOS occurrence. Patients with low L-Ficolin were 9 times (95%CI 3-32) more likely to develop SOS, while patients with high HA and ST2 were 6.5 (95%CI 1.9-22.0) and 5.5 (95%CI 2.3-13.1) times more likely to develop SOS. These three markers also predicted worse day 100 OS [L-Ficolin: HR, 10.0 (95%CI 2.2-45.1), P=0.0002; HA: HR, 4.1 (95%CI 1.0-16.4), P=0.031; ST2: HR, 3.9 (95%CI 0.9-16.4), P=0.04]. L-Ficolin, HA, and ST2 levels measured as early as three days post-HCT improved risk stratification for SOS occurrence and OS and may guide risk-adapted preemptive therapy. gov NCT03132337. NICHD P50HD090215, R01HD074587, NCI R01CA168814 and NHLBI K24HL156896.

(110) Evaluation of Men Under 35 Who Underwent Penile Implant Surgery

Abstract Introduction Erectile Dysfunction (ED) has become an increasingly common disorder in young adult males. There are multiple etiologies of ED ranging from vascular, neurogenic, and structural causes. Often times, ED presenting in young men is psychiatric in nature as opposed to the other causes that typically present in older patients. ED found in young, healthy men with no history of systemic disease or traumatic injury, can be challenging. Past research has shown that men ages 18-35 typically have normal lab results and are treated with PDE-5 inhibitors. However, our data suggests that patients whose symptoms do not improve following the use of PDE-5 inhibitors may have a vascular etiology of ED. Objective Our objective is to determine the prevalence of venous leaks in young adult males who present with ED, but do not respond well to PDE-5 inhibitors. Methods Patients who underwent inflatable penile prosthesis (IPP) surgery for the treatment of ED over a 36-month period under the age of 35 who had failed PDE-5 inhibitors were identified from our database retrospectively. All patients completed an IIEF-5 questionnaire and had a penile doppler ultrasound (PDUS) performed preoperatively. PDUS was used to identify and record cavernous arterial flow signals before and after stimulation. Veno-occlusive ED was described as persistent End Diastolic Velocity (EDV) over 5 cm/sec during all phases of erection. The relationships, according to Doppler diagnosis, IIEF-5 score, SHIM scale, and erection score were evaluated as well as surgical outcomes and patient comorbidities. Results 1,558 patients were evaluated in this series, of whom 32 met inclusion criteria. Patients ages ranged from 18 to 35, with a mean age of 28.4. PDUS determined that 27 (84%) suffered from veno-occlusive disease, while 3 (9%) had arterial insufficiency due to DMI and 2 (7%) had neuropraxia. Of those veno-occlusive disease patients, EDV values ranged from 7.4 to 21.2, with a mean of 13.4, with peak systolic velocity values ranging from 45 to 122cm, with a mean of 97. All patients in this cohort had successful penile prosthesis implantation without complications or need for revision. Conclusions Doppler examination does indeed suggest that patients with cavernous venous occlusive dysfunction have moderate to severe leaks. We strongly recommend a baseline PDUS following PDE-5 inhibitor failure due to the significant prevalence of veno-ccclusive disease in this rare patient population. Furthermore, if veno-occlusive disease is identified during PDUS, we encourage frank discussion of penile prosthesis placement with the patient as well as the severity of veno-occlusive disease and its resultant effect of worsening ED. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: coloplast, boston scientific

Thymosin β4 Exerts a Cytoprotective Function and Attenuates Liver Injury in Murine Hepatic Sinusoidal Obstruction Syndrome after Hematopoietic Stem Cell Transplantation

Hepatic sinusoidal obstruction syndrome (HSOS) is a life-threatening complication that may occur after hematopoietic stem cell transplantation (HSCT). Hepatic sinusoidal endothelial cell (HSEC) injury and liver fibrosis are key mechanisms of HSOS. Thymosin β4 (Tβ4) is an active polypeptide that functions in a variety of pathologic and physiologic states, including inflammation regulation, anti-apoptosis, and anti-fibrosis. In this study, we found that Tβ4 can stimulate HSEC proliferation, migration, and tube formation in vitro via activation of pro-survival signaling AKT (protein kinase B). In addition, Tβ4 resisted γ irradiation-induced HSEC growth arrest and apoptosis in parallel with upregulation of anti-apoptotic protein B cell lymphoma extra-large (Bcl-xL) and B cell lymphoma-2 (Bcl-2), which may be associated with activation of AKT. More importantly, Tβ4 significantly inhibited irradiation-induced pro-inflammatory cytokines in parallel with negative regulation of TLR4/MyD88/NF-κB and MAPK p38. Meanwhile, Tβ4 reduced intracellular reactive oxygen species production and upregulated antioxidants in HSECs. Additionally, Tβ4 inhibited irradiation-induced activation of hepatic stellate cells by downregulating the expression of fibrogenic markers α-SMA, PAI-1, and TGF-β. In a murine HSOS model, levels of circulating alanine aminotransferase, aspartate aminotransferase, total bilirubin, and pro-inflammatory cytokines IL-6, IL-1β, and TNF-α were significantly reduced after administration of Tβ4 peptide; furthermore, Tβ4 treatment successfully ameliorated HSEC injury, inflammatory damage, and fibrosis of the murine liver. Taken together, our findings indicate that Tβ4 stimulates proliferation and angiogenesis of HSECs, exerts a cytoprotective effect, and attenuates liver injury in a murine HSOS model, suggesting that its use may be a potential strategy to prevent and treat HSOS after HSCT.

Mini-hyper-CVD plus inotuzumab ozogamicin, with or without blinatumomab, in the subgroup of older patients with newly diagnosed Philadelphia chromosome-negative B-cell acute lymphocytic leukaemia: long-term results of an open-label phase 2 trial

The outcome of older patients with B-cell acute lymphocytic leukaemia is inferior to that in younger patients due to the adverse disease biology and their inability to tolerate intensive therapy. We aimed to study the long-term outcomes of inotuzumab ozogamicin with or without blinatumomab in combination with low-intensity chemotherapy in these patients. For this open-label phase 2 trial, patients aged 60 years or older with newly diagnosed, Philadelphia-chromosome negative, B-cell acute lymphocytic leukaemia, and an ECOG performance status of 3 or lower were eligible. This study was conducted at the University of Texas MD Anderson Cancer Center. The induction chemotherapy consisted of mini-hyper-CVD and has been published before; inotuzumab ozogamicin was administered intravenously on day 3 of the first four cycles at a dose of 1·3-1·8 mg/m2 in cycle 1, followed by 1·0-1·3 mg/m2 in subsequent cycles (cycles 2-4). Maintenance therapy with dose-reduced POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone) was given for 3 years. From patient 50 onwards, the study protocol was amended to fractionate inotuzumab ozogamicin to a maximum cumulative dose of 2·7 mg/m2 (0·9 mg/m2 during cycle 1 fractionated into 0·6 mg/m2 on day 2 and 0·3 mg/m2 on day 8 of cycle 1, and 0·6 mg/m2 in cycles 2-4 fractionated into 0·3 mg/m2 on day 2 and 0·3 mg/m2 on day 8) followed by blinatumomab for four cycles (cycles 5-8). POMP maintenance was shortened to 12 cycles with one cycle of blinatumomab administered by continuous infusion after every three cycles of POMP. The primary endpoint was progression-free survival and was analysed on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov (NCT01371630) and the present data is from the newly diagnosed, older subgroup of patients treated on the phase 2 portion of this trial; the trial is still enrolling patients. Between Nov 11, 2011, and March 31, 2022, 80 patients were enrolled and treated (32 female and 48 male patients; median age 68 years [IQR 63-72]), 31 of whom were treated after the protocol amendment. With a median follow-up of 92·8 months (IQR 8·8-67·4), the 2-year progression-free survival was 58·2% (95% CI 46·7-68·2) and 5-year progression-free survival was 44·0% (31·2-54·3). At a median follow-up of 104·4 months (IQR 6·6-89·2) for the patients treated before the protocol amendment and 29·7 months (8·8-41·0) for those treated after the protocol amendment, median progression-free survival did not differ significantly between the two groups (34·7 months [95% CI 15·0-68·3] vs 56·4 months [11·3-69·7]; p=0·77). The most common grade 3-4 events were thrombocytopenia in 62 (78%) patients and febrile neutropenia in 26 (32%) patients. Six (8%) patients developed hepatic sinusoidal obstruction syndrome. There were eight (10%) deaths due to infectious complications, nine (11%) from complications related to secondary myeloid malignancy, and four (5%) from sinusoidal obstruction syndrome. Inotuzumab ozogamicin with or without blinatumomab added to low-intensity chemotherapy showed promising activity in terms of progression-free survival in older patients with B-cell acute lymphocytic leukaemia. Further attenuation of the chemotherapy regimen might improve tolerability while maintaining efficacy in older patients. Pfizer and Amgen.

Sinusoidal obstruction syndrome after liver transplantation: A multicenter observational study: Erratum.

Liver Transplantation ():10.1097/LVT.0000000000000124, May 3, 2023. | DOI: 10.1097/LVT.0000000000000124

Results of salvage therapy with mini-hyper-CVD and inotuzumab ozogamicin with or without blinatumomab in pre-B acute lymphoblastic leukemia

BackgroundHistorically, adults with relapsed-refractory acute lymphoblastic leukemia (ALL) experienced poor outcomes with intensive chemotherapy. This mature analysis explores the benefit of the addition of sequential blinatumomab to low-intensity mini-Hyper-CVD chemotherapy with inotuzumab ozogamicin in this setting.MethodsMini-Hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 83% dose reduction) was combined with inotuzumab during the first 4 courses. From Patient #68 and onwards, inotuzumab was given in reduced and fractionated doses, and blinatumomab was added sequentially for 4 courses. Maintenance therapy with prednisone, vincristine, 6-mercaptopurine and methotrexate was given for 12 courses, and blinatumomab for 4 additional courses.ResultsAmong 110 patients (median age, 37 years) treated, 91 (83%) responded (complete response, 69 patients, 63%). Measurable residual disease negativity was documented in 75 patients (82% of responders). Fifty-three patients (48%) received allogeneic stem cell transplantation (SCT). Hepatic sinusoidal obstruction syndrome occurred in 9/67 patients (13%) on the original inotuzumab schedule and in 1/43 (2%) on the modified schedule. With a median follow-up of 48 months, the median overall survival (OS) was 17 months, and the 3 year OS was 40%. The 3 year OS was 34% with mini-Hyper-CVD plus inotuzumab and 52% with additional blinatumomab (P = 0.16). By landmark analysis at 4 months, the 3 year OS was 54%, similar between patients who did or did not receive allogeneic SCT.ConclusionLow-intensity mini-Hyper-CVD plus inotuzumab with or without blinatumomab showed efficacy in patients with relapsed-refractory ALL, with better survival after the addition of blinatumomab.Trial registration The trial was registered on clinicaltrials.gov with the identifier NCT01371630.